Cancer is a group of diseases characterized by uncontrolled cell division (or by an increase of survival or apoptosis resistance) and by the ability of said cells to invade other neighbouring tissues (invasion) and spread to other areas of the body where the cells are not normally located (metastasis) through the lymphatic and blood vessels, circulate through the bloodstream, and then invade normal tissues elsewhere in the body. Depending on whether or not they can spread by invasion and metastasis, tumours are classified as being either benign or malignant: benign tumours are tumours that cannot spread by invasion or metastasis, i.e., they only grow locally; whereas malignant tumours are tumours that are capable of spreading by invasion and metastasis.
There are several types of cancers that can be classified by the type of cell in which it originates and by the location of the cell, i.e., carcinomas, which arise from the cells that cover external and internal body surface, e.g. skin, digestive tract or gland; leukaemia, which starts in blood-forming tissue such as the bone marrow, and causes large numbers of abnormal blood cells to be produced and enter into the bloodstream; Lymphoma, which is a cancer originating in lymph nodes and tissues of the body's immune system; melanoma, which arises in melanocytes; sarcoma, which begins in the connective tissue of bone or muscle; and teratoma, which begins within germ cells.
Cancer can be treated by surgery, chemotherapy, radiation therapy, immunotherapy or other methods. The choice of therapy depends upon the location and grade of the tumour and the stage of the disease.
A significant problem to address in tumour treatment regimens is the desire for a “total cell kill”. This means that the more effective treatment regimens come closer to a total cell kill of all so-called “clonogenic” malignant cells, i.e., cells that have the ability to grow uncontrolled and lead to tumour mass formation that might be removed by the therapy.
Another tumour treatment strategy is the use of an “immunotoxin”, in which an anti-tumour cell antibody is used to deliver a toxin to the tumour cells. However, in common with the chemotherapeutic approaches described above, immunotoxin therapy also suffers from significant drawbacks. For example, antigen-negative or antigen-deficient cells can survive and repopulate the tumour or lead to further metastases. Even if a primary cancer is completely eliminated, a malignant tumour will often be metastatic. The formation of metastases of malignant tumours, initiated from a primary tumour at more or less remote locations of the body, is one of the most serious effects of cancer and one for which a satisfactory treatment protocol is currently unavailable. The currently available methods of cancer therapy have either been of limited success in preventing metastasis or give rise to serious and undesirable side effects.
Although the specific delivery of therapeutic agents, such as anti-cellular agents, toxins and coagulation factors, to tumour mass represents a significant advance in cancer treatment protocols, there is still room for additional or even alternative therapies. The identification of additional targets to allow specific tumour destruction in vivo would naturally be of benefit in expanding the number of targeting options.
The novel therapeutic strategies for treating cancer are now moving towards the use of specific treatments, including monoclonal antibodies (mAbs) against different antigens expressed by tumour cells, which may hopefully cure the disease.
Antigen selection in immunotherapy must take into account either the tumour specificity of the antigen, the antigenic density in the surface of the tumour cells and the antigen modulation or the internalization of the antigen-antibody complex, which can reduce the ability to produce cell death. In most cases, complement-dependent cell lysis (CDC) and antibody-dependent cell-mediated cytotoxicity (ADCC) are believed to be responsible for the clinical utility of the unconjugated mAbs, although the induction of apoptosis or cell cycle arrest could also play a substantial role in other cases.
Cancer cells may express certain molecular receptors. Different studies show that CC chemokine receptor 7 (CCR7) is expressed in different tumour cells, e.g., B-cell chronic lymphocytic leukaemia, non-Hodgkin lymphomas, breast cancer cells, malignant breast tumours, etc. Moreover, it appears that CCR7 receptor plays a role in lymph node metastasis of different cancers, e.g., gastric carcinoma, melanoma, non-small cell lung cancers, T-cell leukaemia cells, etc. Thus, said chemokine receptor (CCR7) can be selected as a possible target for mAb therapy in cancer.
CCR7 is a seven transmembrane-spanning domain G protein coupled receptor (GPCR). The family of G-protein coupled receptors (GPCRs) includes receptors for hormones, neurotransmitters, growth factors, and viruses [Yoshie O, Imai T, Nomiyama H. Novel lymphocyte-specific CC chemokines and their receptors. J Leukoc Biol. 1997; 62:634-644; Kim C H, Pelus L M, White J R, Applebaum E, Johanson K, Broxmeyer H E. CK beta-11/macrophage inflammatory protein-3 beta/EBI1-ligand chemokine is an efficacious chemoattractant for T and B cells. J Immunol. 1998; 160:2418-2424; Dieu M C, Vanbervliet B, Vicari A, et al. Selective recruitment of immature and mature dendritic cells by distinct chemokines expressed in different anatomic sites. J Exp Med. 1998; 188:373-386; Willimann K, Legler D F, Loetscher M, et al. The chemokine SLC is expressed in T cell areas of lymph nodes and mucosal lymphoid tissues and attracts activated T cells via CCR7. Eur J Immunol. 1998; 28:2025-2034; Yoshida R, Nagira M, Imai T, et al. EBI1-ligand chemokine (ELC) attracts a broad spectrum of lymphocytes: activated T cells strongly up-regulate CCR7 and efficiently migrate toward ELC. Int Immunol. 1998; 10:901-910; Sallusto F, Schaerli P, Loetscher P, et al. Rapid and coordinated switch in chemokine receptor expression during dendritic cell maturation. Eur J Immunol. 1998; 28:2760-2769].
A particular case of a leukaemia which tumour cells express a CCR7 receptor is chronic lymphocytic leukaemia (CLL), the most common type of human adult leukaemia. Said leukaemia is a B cell leukaemia characterized by accumulation of a single clone of CD5+ B cells with a great resistance to undergo apoptosis due to deregulation of extracellular or intracellular signalling events implicated in programmed cell death. Despite its very low proliferation index, peripheral blood lymphocyte count reaches values greater than 5×103/μL and leukaemic cells demonstrate a marked tendency to invade lymph nodes, spleen and bone marrow.
The treatment of CLL is based in the use of purine analogues, particularly fludarabine, alone or in association, as frontline regimen. To date, the only therapeutic combination resulting in a higher complete remission rate than that obtained with fludarabine, has been the use of rituximab, an anti-CD20 monoclonal antibody, in association with either fludarabine or fludarabine plus cyclophosphamide. Moreover, molecular remissions in bone marrow aspirates were achieved in CLL patients with the above combinations, raising the possibility that CLL may be potentially curable without stem cell transplantation. Obtaining the best initial response together with the elimination of CLL cells in the inoculum of the patients undergoing autologous transplantation constitute some of the main therapeutic challenges in CLL.
Mantle cell lymphoma (MCL) is an aggressive subtype of B-cell non-Hodgkin's lymphoma. The cells are characterized as CD20+ CD5+ CD23− with a t(11;14) and cyclin D1 overexpression. Patients are usually treated with either rituximab-CHOP (cyclophosphamida, hydroxyl daunorubicin, oncovin and prednisone) followed by stem cell transplantation or rituximab-HyperCVAD (cyclophosphamide, vincristine, adriamycin, and dexamethasone). However, MCL remains without cure in most cases, indicating a clear need for new treatment approaches.
It has been recently demonstrated that CLL patients presenting clinical lymphadenopathy have a higher in vitro migratory response of CLL cells to the ligands of CCR7, the homeostatic chemokines CCL19 (MIP3-β) and CCL21 (6Ckine). Therefore, blocking the entry of the CLL cells into secondary lymphoid tissue with anti-CCR7 mAbs could be another advantage. Also, in this sense, non-lymphoid tumours expressing ectopic CCR7 have the ability to metastasize into secondary lymphoid organs, whereas tumours lacking this molecule or other chemokine receptors involved in the homing to secondary lymphoid organs, present a minimal nodal dissemination.
Therefore, there is a need for additional cancer therapies, in particular, cancer and tumour cells expressing a CCR7 receptor. Advantageously, said therapy should allow specific tumour destruction in vivo by, for example, killing tumour cells, impairing migration and/or blocking dissemination of tumour cells.